NM_005477.3(HCN4):c.2833C>T (p.Pro945Ser) AND Brugada syndrome 8

Clinical significance:Uncertain significance (Last evaluated: Nov 13, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV001244410.1

Allele description [Variation Report for NM_005477.3(HCN4):c.2833C>T (p.Pro945Ser)]

NM_005477.3(HCN4):c.2833C>T (p.Pro945Ser)

Gene:
HCN4:hyperpolarization activated cyclic nucleotide gated potassium channel 4 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
15q24.1
Genomic location:
Preferred name:
NM_005477.3(HCN4):c.2833C>T (p.Pro945Ser)
HGVS:
  • NC_000015.10:g.73323260G>A
  • NG_009063.1:g.51005C>T
  • NM_005477.3:c.2833C>TMANE SELECT
  • NP_005468.1:p.Pro945Ser
  • NC_000015.9:g.73615601G>A
  • NM_005477.2:c.2833C>T
Protein change:
P945S
Molecular consequence:
  • NM_005477.3:c.2833C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Brugada syndrome 8 (BRGDA8)
Identifiers:
MONDO: MONDO:0013148; MedGen: C2751083; Orphanet: 130; OMIM: 613123

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001417630Invitaecriteria provided, single submitter
Uncertain significance
(Nov 13, 2019)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

A novel trafficking-defective HCN4 mutation is associated with early-onset atrial fibrillation.

Macri V, Mahida SN, Zhang ML, Sinner MF, Dolmatova EV, Tucker NR, McLellan M, Shea MA, Milan DJ, Lunetta KL, Benjamin EJ, Ellinor PT.

Heart Rhythm. 2014 Jun;11(6):1055-1062. doi: 10.1016/j.hrthm.2014.03.002. Epub 2014 Mar 4.

PubMed [citation]
PMID:
24607718
PMCID:
PMC4130372

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Invitae, SCV001417630.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

This sequence change replaces proline with serine at codon 945 of the HCN4 protein (p.Pro945Ser). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and serine. This variant is present in population databases (rs778739758, ExAC 0.01%). This variant has been reported in the literature in one individual affected with atrial fibrillation (PMID: 24607718). One experimental study has shown that this missense change does not affect negatively the function of the HCN4 protein (PMID: 24607718). In summary, this variant is a rare missense change that has been shown not to affect protein function. It has been reported in both the population and affected individuals, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 7, 2021

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